An inflammatory response, a defensive mechanism of the body, consists of a highly sophisticated biological signal transduction triggered upon immonological perception of inflammations or injuries and is mediated by various inflammatory cytokines. In general, a disease that disrupts normal tissues as a result of abnormality in such an inflammatory response is called ‘an inflammatory disease’ and extensive researches have been performed worldwide to elucidate the details of its mechanism. Further, the increase of inflammatory cytokines is related to various autoimmune diseases.
Inflammation-related signal transduction system is a series of phosphorylation-dephosphorylation chain reaction and is largely divided into three stages: 1) the initial stage of binging of an inflammation signal in a biomembrane with a biomembrane receptor thereby triggering a series of signal transduction chain reaction; 2)the terminal stage of controlling expression of a gene encoding an inflammation-related protein by means of transcription factors within a nucleus; and 3) an intermediate stage which consists of a series of signal transduction chain reactions that link between the intial stage and the terminal stage.
Examples of well-known inflammation signal factor at the initial stage are tumor necrosis factor (TNF; also referred to as TNF-α) and interleukin-1 (IL-1). Examples of well-known inflammation signal factor at the terminal stage are activating protein-1 (AP-1; activating protein-1), nuclear transcription factor kappa B (NFkB) and nuclear factor of activated T cells (NFAT). The chain reactions at the intermediate stage are not well identified but it appears that lipocortin, cyclooxygenase-1, 2, and PLA2 are involved in this stage.
Referring to inflammation-causing factors, TNF-α, produced mainly in activated macrophage and T cells, is the most powerful inflammatory cytokine and stimulates the production of other inflammatory cytokines such as IL-1, IL-6 and IL-8 as well as transcription factors such as NK-kB and c-jun/Ap-1. In fact, TNF-α is related with the development of inflammatory diseases or immune-related diseases such as toxic shock syndrome, insulin-dependent diabetes, multiple sclerosis, rheumatic arthritis, osteoarthritis, Crohn's disease and ulcerative colitis. In particular, TNF-α is also related with chronic inflammatory diseases such as psoriatic arthritis, psoriatis, ankylosing spondylitis, adult-onset Still's disease, polymyositis, dermatomyositis, and vasculitis such as Behcet disease and Wegener's granulomatosis Behcet disease and Wegener's granulomatosis. IL-1 is also a powerful inflammatory cytokine comparable to TNF-α and increases the expression of genes of PLA2 2 type, COX-2 and iNOS, and as a result, elevates the production of PAF, PGE2 and NO, thereby inducing inflammatory responses. IL-1α and IL-1β are both related with auto-immune diseases such as rheumatic arthritis and insulin-dependent diabetes. IL-1β, like the TNF-α, is also an important mediator of septic shock and cardioopulmonary failure, acute respiratory syndrome and multiple organ failure. IL-6 is a multi-functional cytokine produced in various cells, and is related with diseases such as multiple myeloma, psoriatis, post-menopausal osteoporosis, CNS trauma, viral and bacterial meningitis, Castleman's disease, glomerulonephritis, AIDS dementia complex, a particular neuronal disease such as Altzheimer's disease, a particular leukemia, and systemic erythematosus lupus. IFN-γ is primarily produced by T cells and NK cells and is related with Graft-versus-Host disease, asthma, and other inflammatory diseases such as atopic disease. Further, IL-8 is related with diseases such as stroke, cardiac infarction, acute respiratory distress syndrome, post-injury multiple organ, acute glomerulonephritis, dermatitis, purulent meningitis, or other CNS failure, parahemodialysis, and necrotizing enterocolitis.
In addition, prostaglandins are known to play an important role in an inflammatory response. Inhibition of production of prostaglandins, especially PGG2, PGH2 and PGE2, plays a key role in developing an anti-inflammatory agent. For example, production of prostaglandins can be inhibited by inhibiting the cyclooxygenase (COX), which is induced by inflammatory cytokines. Therefore, the production of prostaglandins can be inhibited by inhibiting cytokines.
Accordingly, as stated above, the decrease in cytokines can be a good method to treat inflammatory diseases as well as immune-related diseases.
Recently, the inventors of the present invention succeeded in synthesizing pyridine derivatives with a novel structure and also discovered that these novel derivatives inhibit the production of cytokines involved in inflammatory responses, in particular, they have a superior inhibitory effect on the production of TNF-α, IL-1, IL-6, IFN-γ and PGE2, Consequently, the inventors of the present invention found that the novel compounds synthesized by the present inventors have superior therapeutic effects on diseases such as inflammatory diseases, immune-related diseases, and chronic inflammatory diseases as well as being useful as an agent having an anti-inflammatory and analgesic effect thereby completing the present invention.
Accordingly, in a preferred embodiment, this invention provides novel pyridine derivatives.
In another preferred embodiment, this invention provides a method to prepare the above-mentioned pyridine derivatives.
In another still preferred embodiment, this invention provides a pharmaceutical composition for treating diseases related with cytokines such as inflammatory diseases, immune-related diseases, chronic inflammatory diseases which is also useful as an anti-inflammatory and analgesic agent.